Field of the Invention
The present invention relates to a new device for iontophoresis to deliver ophthalmic compositions (in particular collyriums) preferably containing riboflavin, designed to imbibe the corneal stroma without having to proceed, in order to obtain said imbibition, to the removal of the corneal epithelium (de-epithelization) in the practice of the treatment of keratoconus, or other ectasic corneal disorders, by means of corneal cross-linking of suitable ophthalmic composition.
Description of the Related Art
Keratoconus is a degenerative disease of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual curve. Keratoconus is a genetic disease consisting in a non-inflammatory progressive dystrophy affecting approximately 50 persons in every 100 000 each year, generally young people between 10 and 20 years of age. As disease frequency is higher amongst females, keratoconus etiology appears to be correlated to dysfunctions of endocrine glands (hypophysis and thyroid). It can affect both eyes in approximately 85% of cases and has an evolution that may vary from subject to subject.
Upon onset of this disease, there appears an irregular curvature that modifies the refractive power of the cornea, producing distorsions of images and a confused close and distant vision. The patient complains in any case of a reduction of vision, above all distant vision. The vision continues to regress irreversibly, with a consequent need for frequent change of spectacles, and for this reason it may at first be mistaken for a myopia associated to astigmatism.
On account of the congenital structural weakness of the corneal stroma due to said disease, after some years the cornea progressively tends to wear out and thin out towards the apex. There then occurs an irregular curvature of the cornea, which loses its spherical shape and assumes the characteristic cone shape (keratoconus).
Using the biomicroscope there may be noted a considerable reduction in the corneal thickness at the top of keratoconus. Over time, the top of keratoconus becomes opaque on account of an alteration in the nutriment of that part of the cornea, which in the most acute forms can present a corneal curvature of more than 62D and reach a corneal thickness of even 446 μm (normal central corneal thickness is 500-700 μm).
If the disease is neglected, the top can ulcerate with consequent perforation of the cornea; there appear pain, lacrimation and spasm of the eyelids. These changes of the cornea due to keratoconus produce an alteration in the disposition of the corneal protein, causing micro-scars that further distort the images and in some cases prevent passage of light, thus giving rise to a troublesome dazzling feeling, above all at times of the day when the sun is low on the horizon (sunrise and sunset).
As already mentioned, in order to correct the vision it becomes necessary to change spectacles frequently. Only after the use of spectacles has proven unsatisfactory, in milder forms rigid contact lenses may be applied.
The real problem arises when the cornea affected by keratoconus undergoes considerable thinning or if cicatrization occurs following upon lacerations of the corneal surface, rendering necessary even surgical transplantation of the cornea (keratoplasty).
In 2002 so-called lamellar keratoplasty was introduced in Italy for the treatment of keratoconus, whereby, in practice, not the entire cornea is replaced, but only the outer thickness, i.e., the part affected by the disease.
However, already by 1997 in Germany, in the ophthalmic clinic of the Carl Gustaw Carus University of Dresda, a new safer and less invasive technique was developed, referred to as “corneal cross-linking” (CXL), which uses in particular riboflavin, activated by a UV laser; in 2005 this technique was tested also in Italy and is by now widely used successfully in various Italian eye clinics.
Corneal cross-linking is a minimally-invasive method, which uses riboflavin activated by a UV laser (365-370 nm); the method is painless and is carried out in day-hospital. Cross-linking enables reinforcement of the structure of the cornea affected by keratoconus through the interweaving and increase in links (cross-linking) between the fibers of the corneal collagen. Clinical studies have proved CXL being able to reduce the astigmatism associated to keratoconus as well as to slow down or arrest pathology evolution, thus avoiding the need for transplantation of the cornea. Also other disorders characterized by corneal ecstasia benefit from treatment using the cross-linking method.
Corneal cross-linking is usually carried out by applying a local corneal anaesthesia for making the abrasion of the corneal epithelium (de-epithelization) having a diameter of 8-9 mm. This is followed by a frequent instillation of a 0.1% riboflavin-based ophthalmic solution during 15 minutes, followed by irradiation with ultraviolet (UV-A) emitter during 30 minutes with instillation of riboflavin solution throughout the irradiation operation.
Riboflavin (molecular weight 376, poorly soluble in water), more preferably riboflavin sodium phosphate (molecular weight 456, negatively charged), which is commonly used in corneal cross-linking, is a hydrophilic photosensitizing and photopolymerizing molecule with a poor capacity for diffusing through the epithelium and hence reaching the corneal stroma.
It is therefore necessary to facilitate absorption thereof and complete impregnation of the corneal stroma before starting the irradiation with UV-A, by removing the corneal epithelium (de-epithelization). This procedure can create, albeit rarely, complications at a corneal level, pain, in addition to being a method that renders the task of the ophthalmologist more difficult.
It would hence be desirable to improve the absorption of riboflavin, without having to remove the epithelium of the cornea, hence obtaining a noninvasive corneal cross-linking with elimination or reduction of the anaesthesia and consequent fast healing without pain or possible complications.
Iontophoresis is known as a noninvasive method which allows the penetration of high concentration of ionized molecules, such as drugs, into living tissue driven by an electric current, in fact, applying a current to an ionizable substance increases its mobility across a biological surface. Three principle forces govern the flux caused by the current. The primary force is electrochemical repulsion, which propels species of the same charge through tissues. When an electric current passes through an aqueous solution containing electrolytes and a charged material (for example, the active pharmaceutical ingredient), several events occur:                (1) the electrode generates ions,        (2) the newly generated ions approach/collide with like charged particles (typically the drug being delivered), and        (3) the electrorepulsion between the newly generated ions force the dissolved/suspended charged particles into and/or through the surface adjacent (tissue) to the electrode.        
Continuous application of electrical current drives the active pharmaceutical ingredients significantly further into the tissues than is achieved with simple topical administration. The degree of iontophoresis is proportional to the applied current and the treatment time.
Iontophoresis occurs in water-based preparations, where ions can be readily generated by electrodes. Two types of electrodes can be used to produce ions: (1) inert electrodes and (2) active electrodes.
Each type of electrode requires aqueous media containing electrolytes. Iontophoresis with an inert electrode is governed by the extent of water hydrolysis that an applied current can produce. The electrolysis reaction yields either hydroxide OH− (cathodic) or hydronium H3O+ (anodic) ions. Some formulations contain buffers, which can mitigate pH shifts caused by these ions. The presence of certain buffers introduces like charged ions that can compete with the drug product for ions generated electrolytically, which can decrease delivery of the drug product (and therefore increase the required application time). The electrical polarity of the drug delivery electrode is dependent on the chemical nature of the drug product, specifically its pKa(s)/isoelectric point and the initial dosing solution pH. It is primarily the electrochemical repulsion between the ions generated via electrolysis and the drug product charge that drives the drug product into tissues. Thus, iontophoresis offers a significant advantage over topical drug application, in that it increases drug absorption. The rate of drug delivery may be adjusted by varying the applied current by the person skilled in the art.
Due to the highly effective administration way of the iontophoretic process, ophthalmologist have long recognized the value of iontophoresis in the delivery of curative molecules to the eye and in the treatment of ocular pathologies, as not only the iontophoretic process permits a more rapid medicine application, but it also allows a more localized and more highly concentrated application of drugs.
Several ocular iontophoretic devices have been developed, reported in the literature and known from the prior art.
The U.S. Pat. No. 3,122,137 filed on Oct. 30, 1961 describes an eye iontophoretic device consisting in a eye-glass frame shaped structure of non-conductive material and incorporating a current source adapted to be supported by the area around the eye orbit, in such a way the device cannot be in direct contact to the eye surface. Such device lacks of substance administration precision due to its rudimentary structural and design features.
The U.S. Pat. No. 4,564,016 filed on Aug. 13, 1984 describes an apparatus having a portion in engagement with the eye, consisting of a small application surface (1 mm diameter) applied on sclera and allowing very high current densities for focal iontophoresis. Such apparatus and the relative method are particularly adapted to introduce ionized drugs into the posterior portion of the eye across the cellular barriers protecting the retina such as the conjunctival epithelium and the pigment epithelium, but the current applied by this method are certainly toxic for the concerned tissues.
More recently, the U.S. Pat. No. 6,319,240 filed on May 25, 1999 proposes an improvement of previous apparatus characterized by the presence of containment element, such as a sealed reservoir applied on sclera (with a semi-permeable membrane on application surface) under the eyelid, that is filled with the medicament released under the influence of the electrical current.
The peculiar feature of the invention described in U.S. Pat. No. 6,442,423 filed on May 2, 1999 is an applicator having a receiving portion holding a replaceable hydrogel carrier that is loaded with the drug. The solution provided by this invention ensures that the fluid drug solution is maintained in contact with the eye during the iontophoresis process, in fact handling of fluids to ensure their contact with eye surface is tricky, since fluids leak and form bubbles that reduce the efficacy of iontophoretic process.
The invention described in U.S. Pat. No. 6,154,671 filed on Apr. 1, 1999 relates to a device for transferring active pharmaceutical ingredients into the eyeball by iontophoresis characterized by an active electrode in the reservoir which is a surface electrode arranged facing eye tissues lying at the periphery of the cornea. In this case the transfer achieved by this system takes place through one or more eye tissues lying at the periphery of the cornea over a wide application area.
The matter of the invention disclosed by U.S. Pat. No. 7,164,943 filed on Mar. 6, 2004 relates an irritation-reducing ocular iontophoresis device provided by such features enabling to reduce application time on the eye and consequent irritation.
Furthermore, following technical advances in the iontophoresis field in the last decades occurred, in particular concerning devices and apparatus, currently in research and development and mainly focused on several formulations suitable for delivery by ocular iontophoresis and methods of use thereof.
Use of ophthalmic compositions, possibly associated to riboflavin for corneal cross-linking in the treatment of keratoconus or other corneal ectasic disorders have been described and is matter-subject of the international patent application PCT/IT2009/000392, and relative priority patent application RM2008A00472. Such disclosed riboflavin based compounds facilitate epithelial absorption associated to corneal CXL, avoiding the resort to de-epithelization of the cornea, enabling a non-invasive corneal elimination or reduction of the anaesthesia and consequent fast healing without pain or possible complication for the patients.
It is also known, from WO2007/025244, a kit cleaning system and method is disclosed. One embodiment of the present invention has a photosensitizer solution supplied by a pressurized nozzle to the target site. Specific application of the solution is to an oral or skin surface target site. The photosensitizer solution is illuminated with sensitizing light creating reactive chemical species. Pressure and a solvent having an elevated concentration of oxygen or oxygen species improve the efficiency of the killing of pathogens. Methods of using the system within an oral cavity are also disclosed.
In this document, the active electrode is not transparent to UV light, visible light or IR light.
However, despite the more recent advances in the relevant field, there is still the need of more efficient delivery systems for releasing ophthalmic compositions to imbibe corneal stroma in the practice of corneal cross-linking for the treatment of keratoconus, and of suitable ophthalmic compositions for the treatment of keratoconus specifically formulated to be adapted to the more efficient corneal iontophoresis application as well.